Process for the preparation of carbamates, thiocarbamates and ureas

ABSTRACT

The invention relates to a process for preparing carbamic acid derivatives of formula: ##STR1## in which R 1  or R 2  denotes a hydrogen atom or a substituted or unsubstituted, saturated or unsaturated aliphatic, cycloaliphatic or heterocyclic radical, or R 1  and R 2  together form a ring, and Y denotes OR, SR, ##STR2## groups, R being a substituted or unsubstituted, saturated or unsaturated aliphatic or cycloaliphatic radical, or a substituted or unsubstituted aromatic radical, R 3  and R 4  denote a hydrogen atom or an aliphatic, cycloaliphatic, araliphatic, aromatic or heterocyclic radical or together form a ring, and R 6  and R 7  denote a saturated or unsaturated, substituted or unsubstituted aliphatic or cycloaliphatic radical, a hydrogen atom, an alkylthio radical or an alkyloxy radical. 
     According to the process, a compound of formula ##STR3## is reacted with an α-halogenated derivative of formula ##STR4## at a temperature of -5° to 150° C. in the presence of an acceptor for hydrohalic acid. 
     The carbamates, thiocarbamates or ureas obtained are very useful, especially as pesticides.

The invention relates to a new process for preparing carbamic acidderivatives. More specifically, it relates to a process for preparingderivatives of formula: ##STR5## in which Y denotes an alcohol,mercaptan or amine residue, which derivatives are consequentlycarbamates, thiocarbamates or ureas.

The processes most commonly used for preparing these compounds are, forexample, for carbamates and thiocarbamates, the reaction of achloroformate or thiochloroformate with an amine, as described in thearticle in Chemical Review, 1964, 64, pages 656-663, or that of acarbamyl chloride or an isocyanate with an alcohol, phenol or mercaptan(Grignard: Traite de Chimie Organique, volume XIV, page 20-31).

As regards ureas, these are most frequently obtained by reacting anisocyanate or a carbamyl chloride with an amine. When they aresymmetrical they can also be prepared by phosgene treatment of an amine(Grignard: volume XIV, pages 85, 30).

However, these various processes do not always enable the desiredcompounds to be prepared, or they are sometimes difficult to implement.

Some starting materials are:

unstable, as is the case with a number of chloroformates such as, forexample, furfuryl, tert-butyl and p-methoxybenzyl chloroformates;

toxic, such as isocyanates, phosgene and especially light carbamylchlorides which are carcinogenic,

or pollutant, such as light thiochloroformates.

Research has been carried out to find new routes.

A few compounds have been prepared by reacting dimethyl carbonate orethylphenyl carbonate with aniline in the presence of a catalyst such asuranyl nitrate, but the yields are very low, the mixture has to beheated to a high temperature (100°; U.S. Pat. No. 3,763,217), andby-products are obtained in substantial quantities.

Diphenyl carbonate does not react with amines to give a carbamate exceptin the presence of a catalyst such as 2-hydroxypyridine [Noboru Yamazakiand Todao Igudi, Fukuji Higashi, Journal of Polymer Science, vol. 17,pages 835-841 (1979)].

Other carbamation agents have been proposed such as:

azides. Synthesis of these is performed in several stages and isawkward. They can decompose explosively, like BOC azide (Angew, Chem.,Ind. Ed. Engl. 16 1977 no. 2),

several trials have been performed with very special carbonates such asmixed p-nitrophenyl carbonates. The by-products obtained are difficultto remove,

bicarbonates. Synthesis of these is very awkward and expensive. This isparticularly the case with tert-butyl bicarbonate. Moreover, aprotective residue is lost,

fluoroformates, the preparation of these is difficult however because itdemands the use of non-commercial starting materials which are awkwardto handle, such as ClCOF or BrCOF.

The reaction of some carbamates with amines has been studied. The ureais only obtained after heating to high temperatures of the order of 150°to 230° and on condition that a catalyst is used (Phillip Adams andFranck A. Baron, Chemical Review, 1965, page 574).

In these various processes, an alcohol or a phenol is always formedwhich is very often difficult to remove, and the reaction is reversible.

In some cases, it is absolutely impossible to prepare the urea. Thus,when ethyl N-imidazolecarbamate is reacted with ethylamine, ethylN-ethylcarbamate and imidazole are obtained, and not the urea.

This brief survey shows the limits of the conventional processes and themeagre results obtained by the new routes.

It was hence desirable that a general process should be available forpreparing carbamic acid derivatives which was easier to implement bothas regards the use of less dangerous starting compounds and also asregards the working conditions and the removal of by-products.

The process according to the present invention is applicable to thepreparation of a large number of carbamic acid derivatives, and isespecially suitable when the other routes leading to these derivativesare unsuitable.

The invention relates to a process for preparing carbamic acidderivatives of general formula: ##STR6## in which R¹ and R², which maybe identical or different, denote:

a hydrogen atom,

a substituted or unsubstituted, saturated or unsaturated, linear orbranched aliphatic or araliphatic radical,

a substituted or unsubstituted, saturated or unsaturated cycloaliphaticradical,

a substituted or unsubstituted, saturated or unsaturated heterocyclicradical,

or together form with the nitrogen atom to which they are bound asaturated or unsaturated, substituted or unsubstituted ring which cancontain one or more heteroatoms and which can form part of a ringsystem. Y denotes OR, SR, ##STR7## groups in which R denotes asubstituted or unsubstituted, saturated or unsaturated, linear branchedaliphatic or araliphatic radical, a substituted or unsubstituted,saturated or unsaturated cycloaliphatic residue, or a substituted orunsubstituted aromatic residue, R³ and R⁴, which may be identical ordifferent, denote a hydrogen atom, a substituted or unsubstituted,saturated or unsaturated aliphatic, araliphatic, cycloaliphatic orheterocyclic radical, or a substituted or unsubstituted aromaticradical, or together form with the nitrogen atom to which they are bounda saturated or unsaturated, substituted or unsubstituted heterocyclewhich can contain 1 or more other hetero atoms, and R⁶ and R⁷, which maybe identical or different, denote a saturated or unsaturated,substituted or unsubstituted, linear or branched aliphatic orcycloaliphatic radical, or denote, but not at the same time, a hydrogenatom, an alkylthio radical or an alkyloxy radical.

This process consists in reacting, in the presence of an acceptor forhydrohalic acid at a temperature of between -5° and 150°, ahydrogen-containing amino compound of formula: ##STR8## with anα-halogenated derivative of carbonic acid of formula: ##STR9## in whichR¹, R² and Y have the above significance, X denotes a fluorine, chlorineor bromine atom and R⁵ denotes a hydrogen atom, a substituted orunsubstituted, saturated or unsaturated, aliphatic, araliphatic orcycloaliphatic residue or a substituted or unsubstituted aromaticresidue.

The reaction can be performed in the presence or absence of a solvent.

The reaction scheme can be written as follows: ##STR10##

It is observed that, surprisingly, HX is eliminated but this is notaccompanied by attachment of the amine residue ##STR11## to the carbonwhich bears the halogen to form: ##STR12## as would normally beexpected, and as is the case, for example, in the reaction of anα-chlorinated carbonate with an acid: ##STR13## (ASTRA--Patent FR No.2,201,870)

In contrast, according to our process, there is cleavage of theα-halogenated derivative, attachment of the ##STR14## group to theresidue of the amino compound and formation of the aldehyde R⁵ CHO.

As starting hydrogen-containing amino compound of formula: ##STR15##ammonia and the majority of known primary or secondary amines can beused.

When R¹ or R² denotes an aliphatic radical, it preferably contains from1 to 20 carbon atoms. R¹ and R² can also signify a cycloaliphatic oraraliphatic radical which can contain up to 50 carbon atoms, for examplea benzyl radical, or together they can form a heterocycle, for example apiperidino, morpholino or imidazolyl ring.

The substituents of R¹ and R² can be various groups such as hydrocarbongroups or acid, alcohol, ester, ether, mercapto or amino functionalgroups.

As useful amines, there may be mentioned methylamine, diethylamine,di-n-butylamine, isobutylamine, n-octylamine, ethanolamine, benzylamine,N-methyl-N-benzylamine, piperidine, imidazole, hexamethyleneimine,morpholine and diethanolamine.

The natural or synthetic, optically active or inactive or racemic aminoacids used in peptide synthesis are also very suitable.

There may be mentioned, for example, L-phenylalanine, L-proline,glycine, L-tyrosine, L-serine, L-aspartic acid, proline, ethyl glycinateand phenylglycine.

The second starting compound used can be an α-halogenated carbonate,thiocarbonate or carbamate. It is preferably α-chlorinated.

Preparation of this compound may be accomplished by various knownprocesses, for example, for chlorinated derivatives, by reacting anα-chlorinated chloroformate of formula: ##STR16## with a hydroxylatedcompound or a mercaptan, as described in the article by M. Matzner, R.Kurkjy and R. J. Cotter [Chem. Rev. 64, pages 651-654 (1964)], or withan amine, by the process described in European patent application Nos.45,234 or 83/401766.7.

α-Chlorinated chloroformates are themselves prepared very simply by theprocess of phosgene treatment of aldehydes claimed in European patentapplication No. 40,153.

The radical R⁵ is preferably a light radical such as an aliphaticradical consisting of 1 to 4 carbon atoms, which can be substituted,preferably with halogen atoms and especially chlorine atoms. Methyl andtrichloromethyl radicals are especially highly valued.

The radical R of the carbonate or thiocarbonate is very variable. Thiscan be

an aliphatic radical preferably containing from 1 to 12 carbon atoms,such as a methyl, ethyl or tert-butyl radical, which can be substituted,for example, with a heterocyclic radical such as furyl,

an araliphatic radical, for example benzyl,

a substituted or unsubstituted aromatic nucleus which may or may notform part of a ring system, such as phenyl or2,3-dihydro-2,2-dimethyl-7-benzofuranyl.

The radical R, whichever its significance, can be substituted with oneor more groups ##STR17##

It is, in particular when the starting amine is an amino acid, one ofthe groups commonly used in peptide synthesis for protecting the aminogroup, such as tert-butyl, benzyl, para-nitrobenzyl, 9-fluorenylmethyl,2,2,2-trichloroethyl, trimethylsilylethyl or furfuryl. α-Chlorinated andtert-butyl carbonates are partiularly highly valued in this case.

R³ and R⁴ present in the starting α-chlorinated carbamate denote, forexample, a hydrogen atom or a methyl radical, or form together and withthe nitrogen atom to which they are attached an imidazolyl ring. Thus,α-chloroethoxycarbonylimidazole and 1,2,2,2-tetrachloroethylN-methylcarbamate are especially highly valued.

R⁶ and R⁷ denote, in particular, a hydrogen atom, a methylthio radical,a C₁ to C₁₂ aliphatic radical or a cycloaliphatic radical which cancontain 30 carbon atoms. The substituents of R⁶ and R⁷ can behydrocarbon radicals or groups containing hetero atoms, especiallysulphur.

Since a release of halogen hydracid HX takes place during the reaction,the presence of an acceptor for acid is necessary for the removal ofthis acid.

The acceptor for acid can be an organic or inorganic base.

Among the preferred bases, there may be mentioned sodium hydroxide orpotassium hydroxide, sodium carbonate or bicarbonate or potassiumcarbonate or bicarbonate, magnesium oxide, and sodium sulphite, whichare generally used in the form of aqueous solutions, tertiary aminessuch as triethylamine, pyridine or N,N-dimethylaniline, and the startingamine itself of formula ##STR18##

The amount of basic substance introduced into the medium should besufficient to neutralise all the acid released. A slight excess relativeto the stoichiometric quantity is preferably used.

The reaction according to the invention is preferably performed insolvent medium. One or more solvents are generally used which are inerttowards the reagents. They are preferably chosen from chlorinatedaliphatic solvents, such as dichloromethane or 1,2-dichloroethane,cyclic or acyclic ethers, for example tetrahydrofuran or dioxane,acetone, pyridine, acetonitrile, dimethylformamide or alcohols such asethanol or tert-butanol. The reaction medium can contain a certainamount of water, necessary, for example, for the dissolution ofinorganic bases.

The reaction temperature depends on the nature of the solvent and thereactivity of the starting compounds. It is between -5° and 150° C. Itis most frequently between 0° and 30° C. for the reaction of carbonatesand thiocarbonates with amines, and between 30° and 100° C. for thereaction of carbamates.

The starting compounds are generally used in stoichiometric amounts. Itis preferable to use a slight excess of one of the two reagents.

When the starting amine is used as acceptor for acid, at least twoequivalents of amine are used per ##STR19## group to be converted.

The order in which the reagents are introduced is not a basic feature ofthe invention. However, when the amine is primary and is also used asacceptor base for acid, it is preferable to introduce it after the otherstarting compound.

The process of the invention enables many compounds to be readilyobtained, some of which are prepared with great difficulty by thecustomary methods. These compounds are very useful as pharmaceuticalproducts, as pesticides such as CARBOFURAN, 3,4-dimethylphenylN-methylcarbamate, ALDICARB, CARBARYL among carbamates, BUTYLATE, EPTC,MOLINATE among thiocarbamates, and CHLORTOLURON and MONURON among ureas,or as intermediates in peptide synthesis such as amino acid carbamates,and there may be mentioned, for example, the synthesis of ASPARTAME(Tetrahedron, volume 39, No. 24, pages 4121 to 4126, 1983, B. Yde etal.).

The invention is illustrated by the examples which follow.

EXAMPLE 1 Preparation of ethyl N,N-di-n-butylcarbamate ##STR20##

A solution of 26 g (0.2 mole) of di-n-butylamine in 20 ml of anhydroustetrahydrofuran (THF) is added dropwise to a solution of 15.2 g (0.1mole) of α-chloroethyl ethyl carbonate ##STR21## in 80 ml of THF.

The addition is carried out with stirring at 20° C. The reaction isslightly exothermic and the formation of a precipitate of dibutylaminehydrochloride is observed. The mixture is stirred for 2 hours at 20° C.,the precipitate removed by filtration and the THF evaporated.

The residue is taken up in 200 ml of dichloromethane, and the solutionis washed with 50 ml of aqueous saturated KHCO₃ solution and then with50 ml of water. After the solution is dried over magnesium sulphate, thesolvent is removed by evaporation and the residual mixture distilledunder reduced pressure.

15.1 g (75% yield) of the expected carbamate are thus obtained.

Boiling point (b.p.) 78°-80° C./40 Pa (0.3 mm Hg).

IR :νC=0: 1700 cm⁻¹.

¹ H NMR: 0.9-1.7 ppm (17H) complex C--CH₂ --CH₃ ; 3.2 ppm (4H) tripletN--CH₂ ; 4.1 ppm (2H) quartet O--CH₂.

EXAMPLE 2 Preparation of ethyl N-n-octylcarbamate ##STR22##

The solution of 7.6 g (0.05 mole) of α-chloroethyl ethyl carbonate in 10ml of THF cooled to 5°-10° C. is added to a solution, also cooled to5°-10° C., of 12.9 g (0.1 mole) of n-octylamine in 40 ml of THF.

After the addition has been performed with stirring, the mixture isallowed to return to room temperature and is maintained at thistemperature for 2 hours with stirring.

After the precipitate has been removed by filtration and the solventevaporated, the residue is taken up in 50 ml of ethyl ether, thesolution filtered again and the ether phase washed with 50 ml of water.

After the solution is dried over magnesium sulphate, the solvent isremoved by evaporation and the residual mixture distilled under reducedpressure.

8.64 g (86% yield) of the expected carbamate are thus obtained.

B.p. 110° C./40 Pa (0.3 mm Hg).

IR: νC=0: 1700 cm⁻¹ ; νN-H: 3300cm⁻¹.

¹ H NMR: 0.1-1.7 ppm (18H) complex (CH₂)_(n) CH₃ ; 3.2 ppm (2H) quartetN--CH₂. 4.1 ppm (2H) quartet O--CH₂. 5.2 ppm (1H) complex ##STR23##

EXAMPLE 3 Preparation of ethyl N-n-octylcarbamate

In a reactor, there are introduced 6.5 g (0.05 mole) of n-octylamine, 30ml of THF, 10 ml of water and 10 g of potassium carbonate K₂ CO₃. Whilemaintaining the temperature at 5°-10° C., 7.6 g (0.05 mole) ofα-chloroethyl ethyl carbonate dissolved in 5 ml of THF are then addeddropwise and with stirring.

The mixture is allowed to return to room temperature and is maintainedwith stirring at this temperature for 1 hour. 50 ml of water saturatedwith sodium chloride are added, the mixture is extracted with twice 40ml of ethyl ether, and the ether phases are combined and dried overmagnesium sulphate.

After removal of the solvent by evaporation and distillation underreduced pressure, 7.4 g (74%) of the expected carbamate are collected.

B.p. 110°-112° C./40 Pa (0.3 mm Hg).

EXAMPLE 4 Preparation of ethyl N,N-di-n-butylcarbamate

To a solution of 6.5 g (0.05 mole) of di-n-butylamine and 5.56 g (0.055mole) of triethylamine in 40 ml of THF, 8.4 g (0.055 mole) ofα-chloroethyl ethyl carbonate dissolved in 10 ml of THF are addeddropwise and with stirring while the temperature is maintained at 5°-10°C.

The mixture is allowed to return to room temperature, and is maintainedwith stirring at this temperature for 2 hours.

After removal of the precipitate by filtration, evaporation of thesolvent and distillation under reduced pressure, 6.3 g (63% yield) ofthe expected carbamate are collected.

B.p. 76° C./26.6 Pa (0.2 mm Hg).

EXAMPLE 5 Preparation of tert-butyl N-n-octylcarbamate ##STR24## (a)Synthesis of α-chloroethyl tert-butyl carbonate

In a reactor cooled to +5° C., there are introduced 600 ml ofdicloromethane, 43.7 g (0.59 mole) of tert-butanol and 94.7 g (0.66mole) of α-chloroethyl chloroformate. 57 g (0.72 mole) of pyridine arethen added dropwise and with stirring while the temperature ismaintained at between 10° and 20° C. The mixture is stirred for 4 hoursat room temperature.

The reaction mixture is washed with 100 ml of aqueous 1N hydrochloricacid solution, 200 ml of saturated Na₂ CO₃ solution, and with twice 100ml of iced water. The organic phase is collected and dried overmagnesium sulphate.

After evaporation of the solvent and distillation under reducedpressure, 91.5 g (86%) of α-chloroethyl tert-butyl carbonate areobtained.

B.p. 88° C./2.7 kPa (20 mm Hg).

IR: νC=0: 1750 cm⁻¹.

¹ H NMR: 1.5 ppm (9H) (CH₃)₃ --C-- singlet; 1.8 ppm (3H) doublet##STR25## 6.4 ppm (1H) quartet ##STR26##

(b) Reaction of α-chloroethyl tert-butyl carbonate with n-octylamine

A solution of 52 g (0.4 mole) of n-octylamine in 60 ml of anhydrous THFis added dropwise to a solution of 36.2 g (0.2 mole) of α-chloroethyltert-butyl carbonate in 120 ml of THF. The addition is carried out withstirring at +10° C.

The mixture is stirred for approximately 15 hours at room temperature,the insoluble compounds are removed by filtration and the THFevaporated. The residue is taken up in 400 ml of dichloromethane, andthe solution is washed with 100 ml of 1N aqueous HCl solution, 200 ml ofwater, 100 ml of saturated aqueous KHCO₃ solution and then with 100 mlof water.

After the solution is dried over magnesium sulphate, the solvent isremoved by evaporation and the residual mixture distilled under reducedpressure.

36.52 g (80% yield) of the expected carbamate are thus obtained.

B.P. 142° C./200 Pa (1.5 mm Hg).

IR: νC=0: 1690 cm⁻¹ ; νNH: 3340 cm⁻¹.

¹ H NMR: 0.1-1.3 ppm (15H) complex C--(CH₂)n CH₃ ; 1.4 ppm (9H) singlet(CH₃)₃ --C; 3.0 ppm (2H) quartet CH₂ --N; 4.7 ppm (1H) complex ##STR27##

(c) Preparation of chloromethyl tert-butyl carbonate

The procedure is as in Example 5 (a). Starting with 7.4 g (0.1 mole) oftert-butanol, 15.48 g of chloromethyl chloroformate and 8.1 ml ofpyridine, 9.2 g (55%) of tert-butyl chloromethyl carbonate are obtained.

B.p. 82° C./2 kPa (15 mm Hg).

¹ NMR: 1.4 ppm (CH₃)₃ --C singlet; 5.8 ppm CH₂ --Cl singlet.

IR: νC=0: 1750 cm⁻¹.

(d) Reaction of chloromethyl tert-butyl carbonate with n-octylamine

The procedure is as in 5 (b), but 1-chloroethyl tert-butyl carbonate isreplaced by chloromethyl tert-butyl carbonate. Starting with 6.5 g ofn-octylamine and 8.5 g of chloromethyl tert-butyl carbonate, 4.3 g (38%)of tert-butyl N-n-octylcarbamate, are obtained identical to thatobtained above (5 (b)).

EXAMPLE 6 Preparation of furfuryl N-n-octylcarbamate ##STR28## (a)Synthesis of α-chloroethyl furfuryl carbonate

The procedure as in Example 5 (a), but with 0.22 mole of α-chloroethylchloroformate introduced dropwise into a solution of 0.2 mole offurfuryl alcohol and 0.24 mole of pyridine in 200 ml of dichloromethane.

35.55 g (87% yield) of α-chloroethyl furfuryl carbonate are collected.

B.P. 94°-98° C./13.3 Pa (0.1 mm Hg).

IR: νC=0: 1750 cm⁻¹.

¹ H NMR: 1.8 ppm (3H) doublet CH₃ --C; 5.2 ppm (2H) singlet CH₂ O;6.3-6.6 ppm (3H) complex H--C═ and ##STR29## 7.5 ppm (1H) complex

(b) Reaction of α-chloroethyl furfuryl carbonate with n-octylamine

The procedure is as in Example 5 (b), but with 10.2 g (0.05 mole) of theabove carbonate in 30 ml of THF, and 12.9 g (0.1 mole) of n-octylaminein 15 ml of THF.

11.05 g (87% yield) of the expected carbamate are obtained.

B.p. 162° C./66.6 Pa (0.5 mm Hg), melting pt. (m.p.) 29° C.

IR: νC=0: 1700 cm⁻¹ ; νNH: 3340 cm⁻¹.

¹ H NMR: 0.7 to 1.5 ppm (15H) complex (CH₂)n CH₃ 3.1 ppm (2H) quartetCH₂ N 4.9 ppm (1H) broad complex NH 5.0 ppm (2H) singlet CH₂ O 6.4 ppm(2H) complex H--C═7.4 ppm (1H) complex ##STR30##

EXAMPLE 7 Preparation of furfuryl N-n-octylcarbamate

In a reactor, there are introduced 6.5 g (0.05 mole) of n-octylamine, 30ml of THF and 20 ml of 5M aqueous K₂ CO₃ solution. With the temperaturemaintained at 5°-10° C., 11.25 g (0.055 mole) of α-chloroethyl furfurylcarbonate are then introduced dropwise and with stirring.

The mixture is allowed to return to room temperature and is maintainedwith stirring at this temperature for 18 hours. 50 ml of water saturatedwith sodium chloride are added, the mixture is extracted with twice 40ml of ethyl ether and the ether phases are combined and dried overmagnesium sulphate.

After removal of the solvent and distillation under reduced pressure,9.5 g (75%) of the expected carbamate are collected.

B.p. 142° C./26.6 Pa (0.2 mm Hg).

EXAMPLE 8 Preparatioon of benzyl N-n-octylcarbamate ##STR31## (a)Synthesis of α-chloroethyl benzyl carbonate

The procedure is as in Example 5 (a), but with 200 ml ofdichloromethane, 21.6 g (0.2 mole) of benzyl alcohol, 31.6 g (0.22 mole)of α-chloroethyl chloroformate and 0.2 mole of pyridine.

40.5 g (94% yield) of α-chloroethyl benzyl carbonate are thus collected.

B.p. 100° C./66.6 Pa.

IR: νc=0: 1760 cm⁻¹.

¹ H NMR: 1.8 ppm (3H) doublet CH₃ --; 5.2 ppm (2H) singlet CH₂ ; 6.4 ppm(1H) quartet O--CH--Cl; 7.3 ppm (5H) singlet aromatic protons.

(b) Reaction of α-chloroethyl benzyl carbonate with n-octylamine

The procedure is as in Example 5 (b), but with 19.4 g (0.15 mole) ofn-octylamine in 30 ml of THF and 16.2 g (0.075 mole) of the abovecarbonate in 40 ml of THF.

17.7 g (90% yield) of the expected carbamate are obtained.

B.p. 180° C./66.6 Pa (0.5 mm Hg).

M.p. 33°-34° C.

IR: νC=0: 1680 cm⁻¹ ; νNH: 3380 cm⁻¹.

¹ H NMR: 0.7 to 1.5 ppm (15H) complex (CH₂)n CH₃ 3.1 ppm (2H) quartetCH₂ N 4.8 ppm (1H) singlet NH 5.1 ppm (2H) singlet ##STR32## 7.3 ppm(5H) singlet aromatic protons

EXAMPLE 9 Preparation of phenyl N-isobutyl carbamate ##STR33## (a)Synthesis of 60 -chloroethyl phenyl carbonate

The procedure is as in Example 5 (a), but with 500 ml ofdichloromethane, 47 g (0.5 mole) of phenol, 79 g (0.055 mole) ofα-chloroethyl chloroformate and 0.5 mole of pyridine.

94.23 g (94%) of α-chloroethyl phenyl carbonate are thus collected.

B.p. 110° C./66.6 Pa (0.5 mm Hg).

IR: νC=0: 1770 cm⁻¹.

¹ H NMR: 1.7 ppm (3H) doublet CH₃ ; 6.35 ppm (1H) quartet CH--Cl; 7.0 to7.3 ppm (5H) complex aromatic protons.

(b) Reaction sof α-chloroethyl phenyl carbonate with isobutylamine

The procedure is as in Example 7, but with 7.3 g (0.1 mole) ofisobutylamine, 35 ml of 5M aqueous K₂ CO₃ solution and 20.1 g (0.1 mole)of the above carbonate.

After removal of the solvent and recrystallisation in petroleum ether,12.5 g (65%) of the expected product are obtained.

M.p. 66°-67° C.

IR: νC=0: 1710 cm⁻¹ ; NH: 3400 cm⁻¹.

¹ H NMR: 0.9 ppm (6H) doublet CH₃ ; 1.8 ppm (1H) multiplet ##STR34## 3.1ppm (2H) triplet CH₂ --N; 5.3 ppm (1H) broad singlet NH; 7.0 to 7.3 (5H)complex aromatic protons.

EXAMPLE 10 Preparation of tert-butyloxycarbonylpiperidine ##STR35##

The procedure is as in Example 7, but with 8.5 g (0.1 mole) ofpiperidine, 60 ml of THF, 20 ml of saturated aqueous K₂ CO₃ solution and0.11 mole of α-chloroethyl tert-butyl carbonate.

The mixture is stirred for only 2 hours. 14.8 g (80%) of the expectedcarbamate are collected.

B.p. 96°-98° C./2 kPa (15 mm Hg).

IR: νC=0: 1690 cm⁻¹.

¹ H NMR: 1.3-1.6 ppm, (15H) --CH₂ --, CH₃ --3.3 ppm (4H) CH₂ N.

EXAMPLE 11 Preparation of S-ethyl N-n-octyl thiocarbamate ##STR36## (a)Preparation of α-chloroethyl S-ethylthiocarbonate ##STR37##

The procedure is as in Example 5 (a), but with 31.5 g (0.22 mole) ofα-chloroethyl chloroformate introduced into a solution of 12.4 g (0.2mole) of ethanethiol and 15.8 g (0.2 mole) of pyridine in 200 ml ofdichloromethane.

21.1 g (62.5%) of α-chloroethyl S-ethyl thiocarbonate are obtained.

B.p. 110° C./5.86 kPa (44 mm Hg).

IR: νC=0: 1720 cm⁻¹.

¹ H NMR: 1.3 ppm triplet CH₃ ; 1.75 ppm doublet CH₃ ; 2.8 ppm quartetCH₂ --S; 6.5 ppm quartet O--CHCl.

(b) Reaction of α-chloroethyl S-ethyl thiocarbonate with n-octylamine

The procedure is as in Example 7, but with 6.5 g (0.05 mole) ofn-octylamine, 30 ml of THF, 20 ml of 5M aqueous K₂ CO₃ solution and 8.43g (0.05 mole) of the above thiocarbonate.

5.3 g (49%) of the expected thiocarbamate are thus collected.

B.P. 146°-152° C./66.6 Pa (0.5 mm Hg).

IR: νC=0: 1650 cm⁻¹ ; νNH: 3300 cm⁻¹.

¹ H NMR: 0.7 to 1.6 ppm (18H) complex (CH₂ nCH₃ ; 2.8 ppm (2H) quartetCH₂ S; 3.1 ppm (2H) pseudo-triplet CH₂ N; 3.2 ppm (1H) broad singlet NH.

EXAMPLES 12 TO 19 Preparation of various benzyl carbamates

In these examples, α-chloroethyl benzyl carbonate is reacted accordingto the procedure of Example 7 with various primary or secondary amines.

The temperature conditions and reaction time, the physical properties ofthe products obtained and the yields are shown in Table I.

                                      TABLE I                                     __________________________________________________________________________                                                              Yields of                Amines          Temper-                     Boiling                                                                                purified            Ex. no                                                                             used        Time                                                                              ature                                                                              Products obtained      [melting                                                                               products            __________________________________________________________________________    12                                                                                  ##STR38##  5 h 20° C.                                                                       ##STR39##             175° C./13.3 Pa                                                        [64° C.]                                                                        84%                 13                                                                                  ##STR40##  4 h 20° C.                                                                       ##STR41##             165° C./133.3                                                                   87%                 14                                                                                  ##STR42##  2 h 20° C.                                                                       ##STR43##              96° C./66.7                                                                    99%                 15                                                                                  ##STR44##  2 h 20° C.                                                                       ##STR45##             126° C./66.7                                                                    97%                 16                                                                                  ##STR46##  3 h 20° C.                                                                       ##STR47##             140° C./13.3                                                                    84%                 17                                                                                  ##STR48##  18 h                                                                              20° C.                                                                       ##STR49##             130° C./133.3                                                                   50%                 18   NH.sub.2CH.sub.2 CH.sub.2 OH                                                              5 h 20° C.                                                                       ##STR50##             170° C./66.7                                                                    74%                 19                                                                                  ##STR51##  2 h 20° C.                                                                       ##STR52##             165° C./66.7                                                                    87%                 __________________________________________________________________________

EXAMPLE 20 Preparation of S-ethyl N,N-hexamethylenethiocarbamate(MOLINATE) ##STR53##

The procedure is as in Example 11, reacting α-chloroethyl S-ethylthiocarbonate with hexamethyleneimine.

"MOLINATE" is obtained in a yield of 70% of distilled product.

[B.p. 141° C./1.7 kPa (13 mm Hg)]

EXAMPLE 21 Preparation of tert-butyl N-benzylcarbamate ##STR54## (a)Synthesis of 1,2,2,2-tetrachloroethyl tert-butyl carbonate

9.9 g (0.04 mole) of 1,2,2,2-tetrachloroethyl chloroformate are added ina single portion to a solution of tert-butanol (3 g; 0.04 mole) indichloromethane (50 ml). The mixture is cooled to 0° C. and 3.2 g (0.04mole) of pyridine are added dropwise. The mixture is stirred for 4 hoursat room temperature. 20 ml of iced water are then added, and the organicphase is separated and washed with 20 ml of iced water. It is dried overmagnesium sulphate and the solvent is evaporated. 11.3 g of a whitesolid (yield: 99%) are obtained, the solid is recrystallised inpetroleum ether (87% yield; m.p. 70° C.), and 9.9 g of the purifiedcarbonate are obtained.

B.p. 96° C./866 Pa (6.5 mm Hg).

IR: νC=0: 1770 cm⁻¹.

¹ H NMR: (CDCl₃, TMS): 1.5 (s, CH₃) 6.7 (s, CH).

(b) Reaction of the above carbonate with benzylamine

1.1 g (0.01 mole) of benzylamine is dissolved in 20 ml of THF, and 3 mlof 5M aqueous potassium carbonate solution are added.

2.9 g (0.01 mole) of tert-butyl tetrachloroethyl carbonate dissolved in5 ml of THF are then added at 5° C. The mixture is stirred for 1 hour at20° C., and the organic phase is decanted and washed with 10 ml ofsaturated aqueous NaCl solution. The organic phase is dried, the solventevaporated and the residual mixture distilled: 2.0 g of the expectedcarbamate are obtained (yield: 96%). B.p. 103° C./6.7 Pa (0.05 mm Hg).

The product is recrystallised in petroleum ether, and 1.84 g of theexpected carbamate is obtained (89%). M.p. 54° C. (lit. 53°-54° C.)

EXAMPLE 22 Preparation of tert-butyloxycarbonylimidazole ##STR55##

5 g (17.5 mmol) of tert-butyl 1,2,2,2-tetrachloroethyl carbonatedissolved in 10 ml of THF are added at 0° C. to a solution of imidazole(1.2 g; 17.6 mmol) in THF (20 ml) in the presence of 5M aqueouspotassium carbonate solution (5 ml). The mixture is stirred for 1 hourat 20° C., and the organic phase is decanted and washed with 10 ml ofsaturated aqueous NaCl solution.

After the organic phase is dried and the solvents are evaporated, theresidue obtained is distilled, and 2.55 g of product are obtained (yield86%).

B.p. 64° C./133.3 Pa (1 mm Hg).

M.p. 43° C.

EXAMPLE 23 Preparation of 2,3-dihydro-2,2-dimethyl-7-benzofuranylN-methylcarbamate (CARBOFURAN) (a) Synthesis of 1-chloroethyl2,3-dihydro-2,2-dimethyl-7-benzofuranyl carbonate

21.5 g (0.15 mole) of 1-chloroethylchloroformate are added in a singleportion to a solution of 2,3-dihydro-2,2-dimethyl-7-benzofuranol (24.6g; 0.15 mole) in dichloromethane (150 ml). The mixture is cooled tobetween 0° and 5° C., and 12 g (0.15 mole) of pyridine are addeddropwise. The mixture is stirred for 3 hours at 20° C. The organic phaseis then washed with 2×50 ml of iced water. It is dried over magnesiumsulphate and the solvent is evaporated. A yellow oil is obtained whichis distilled. 34.1 g of the expected carbonate is then recovered (84%yield).

B.p. 127° C./66.6 Pa (0.5 mm Hg).

(b) Reaction of the above carbonate with methylamine

5.4 g (0.02 mole) of the above carbonate are dissolved in THF (20 ml).10 ml of approximately 5M aqueous K₂ CO₃ solution are then added,followed by 1.7 ml (0.02 mole) of a 40% strength solution of methylaminein water. The mixture is stirred for 15 hours at 20° C. The organicphase is decanted and washed with saturated NaCl solution. The solventis evaporated and the product crystallised in methylcyclohexane. 3.5 gof the desired carbamate are obtained (79% yield).

M.p. 148° C.

(c) The procedure is as in (a) followed by (b), but pyridine is replacedby N,N-dimethylaniline and the intermediate carbonate is not distilled.Starting with 16.4 g of 2,3-dihydro-2,2-dimethyl-7-benzofuranol, 16.8 g(76%) of CARBOFURAN are then obtained, M.p. 147° C.

EXAMPLE 24 Preparation of N-methyl-N'-piperidylurea (a) Synthesis of1,2,2,2-tetrachloroethyl N-methylcarbamate

34.7 ml (0.4 mmol) of methylamine (in 40% strength aqueous solution) areadded dropwise to a solution maintained at 0° C. of 49.4 g (0.2 mole) of1,2,2,2-tetrachloroethyl chloroformate in dichloromethane (150 ml). Themixture is then stirred for 2 hours at room temperature. The organicphase is washed with 2×100 ml of water and dried over magnesiumsulphate.

The product crystallises on evaporation of the solvent, and 42.6 g ofthe expected carbamate are obtained (88% yield).

M.p. 105°-106° C.

¹ H NMR: 2.75 (CH₃ --N); 5.2 (NH); 6.7 (CH--Cl).

IR: νC=0: 1760 cm⁻¹.

(b) Synthesis of N-methyl-N'-piperidylurea

4.83 g (0.02 mole) of the carbamate obtained above are dissolved in 30ml of THF and 5 ml of water saturated with K₂ CO₃. 1.7 g (0.02 mole) ofpiperidine is added to this solution maintained at 10° C., and themixture is stirred for 4 hours at room temperature. The organic phase isdecanted and washed with 50 ml of water saturated with NaCl. It is driedover magnesium sulphate, the solvent evaporated and the residuedistilled. 1.8 g of the urea is obtained (63% yield).

B.p. 110° C./6.7 Pa (0.05 mm Hg).

EXAMPLE 25 Preparation of imidazolylcarbonylpiperidine ##STR56## (a)Synthesis of α-chloroethoxycarbonylimidazole

28.6 g (0.2 mole) of chloroethyl chloroformate are added dropwise to asolution of 27.2 g (0.4 mole) of imidazole in 200 ml of dichloromethanecooled in a water bath. The mixture is stirred at room temperature for 4hours, and 50 ml of iced water are then added. The organic phase iswashed with 2×50 ml of water and then dried over magnesium sulphate.After evaporation and distillation, 38.1 g (73%) ofα-chloroethoxycarbonylimidazole [B.p. 80° C./66.6 Pa (0.5 mm Hg)] areobtained in the form of a colourless liquid which crystallisesspontaneously at room temperature, m.p. 50° C. ##STR57##

¹ H NMR: (60 MHz, CDCl₃, TMS) δ: 1.9 (d, CH₃); 6.7 (q, OCH--Cl); 7.05;7.4; 8.2 (3 pseudo-singlets, imidazole).

IR: νC=0 1770 cm⁻¹.

(b) Reaction of α-chloroethoxycarbonylimidazole with piperidine

A solution of 8.5 g (0.1 mole) of piperidine in 10 ml of THF is addeddropwise to a solution of α-chloroethoxycarbonylimidazole (8.75 g; 0.05mole) in 50 ml of THF. This solution is cooled to +5° C. while theaddition is taking place, and then stirred at room temperature.

The piperidine hydrochloride formed is filtered off and the organicphase then washed once with water. After this is dried over magnesiumsulphate and the solvent evaporated, the residual mixture is distilledand 6.2 g (yield: 70%) of the expected product is recovered.

B.p. 134° C./26.6 Pa (0.2 mm Hg).

The liquid obtained crystallises spontaneously in the refrigerator.

M.p. 38° C.

¹ H NMR: 1.5 ppm multiplet (CH₂)₃ ; 3.5 ppm multiplet ##STR58##

    ______________________________________                                        7.0 ppm                                                                       7.15 ppm               imidazole                                              7.8 ppm                                                                       ______________________________________                                    

IR: νC=0 1690 cm⁻¹.

EXAMPLE 26 Preparation of N,N-diethylimidazolecarboxamide ##STR59##

The procedure is as in Example 25 b/, but piperidine is replaced bydiethylamine. 6.5 g of the desired urea are obtained (78% yield).

B.p. 106° C./26.6 Pa (0.2 mm Hg).

M.p. 41° C. (Lit. 38°-43° C.).

¹ H NMR: 1.2 ppm (t, CH₃); 3.4 ppm (q, CH₂ N);

    ______________________________________                                        7.0 ppm                                                                       7.2 ppm               imidazole                                               7.8 ppm                                                                       ______________________________________                                    

IR: νC=0 1690 cm⁻¹.

EXAMPLE 27 Preparation of 2-methyl-2(methylthio)propanalO-[(methylamino)carbonyl]oxime (ALDICARB)

50 ml of toluene and 6.65 g (0.05 mole) of2-methyl-2-(methylthio)propanal oxime are added successively to 5 ml of10N caustic soda. The mixture is stirred for a few moments at roomtemperature and the water is then removed by azeotropic distillation.The mixture is then cooled in an iced water bath and 7.15 g (0.05 mole)of 1-chloroethyl chloroformate are added dropwise. The mixture isstirred for 1 hour at approximately 10°-15° C. to obtain the2-methyl-2(methylthio) propanaloxime 1-chloroethylcarbonate.10 ml(approximately 0.13 mole) of 40% strength aqueous methylamine are thenadded dropwise, and the mixture is stirred for a further hour at thesame temperature. The organic phase is decanted and washed with 10 ml oficed water. The organic phase is dried over magnesium sulphate andevaporated to dryness. 8.7 g of pale brown solid are obtained, m.p.82-90° C. (70% HP_(LC) pure) which can be further purified either bysilica gel chromatography or by chrystallization from isopropylether(63% yield, M.P. 98°-100° C.) HNMR (CDCl₃, 60 MHZ): 1.42 P.P.M/S, 6H)1.92 (S, 3H) 2.92 (D, 3H) 7.54 (S, 1H).

EXAMPLE 28 Synthesis of tert-butyloxycarbonyl-L-aspartic acid

To a solution of 1.33 g (10 mmol) of L-aspartic acid in a dioxane/water(1:1) mixture (30 ml), 4.2 ml (30 mmol) of triethylamine are added, andthe mixture is stirred until solution is complete (approximately 10min). 2.85 g (10 mmol) of tert-butyl 1,2,2,2-tetrachloroethyl carbonateare then added and the mixture is stirred for 6 hours at 20° C. 50 ml ofwater are then added and the mixture is extracted with 2×20 ml of ethylacetate. The aqueous phase is acidified (pH 2-3) with NHCl, and thenextracted with 3×30 ml of ethyl acetate. The extract is washed withsaturated NaCl solution, dried over MgSO₄ and evaporated. The productobtained is crystallised in ethyl acetate and petroleum ether. 1.4 g(60% yield) of the expected acid is obtained. ##STR60##

EXAMPLE 29 Preparation of ethyl furfuryloxycarbonyl-glycinate

2.05 g (10 mmol) of α-chloroethyl furfuryl carbonate are added to asolution of 1.03 g (10 mmol) of ethyl glycinate in 6 ml of THF and 4 mlof 0.5M potassium carbonate solution maintained at between 5° and 10° C.The mixture is allowed to come to room temperature and is stirred for 18hours. 50 ml of water saturated with NaCl are added and the mixture isextracted with 3×40 ml of ethyl ether. The organic phases are combinedand dried over magnesium sulphate. After removal of the solvent anddistillation, 1.5 g (66% yield) of the expected product is collected.

B.p. 144° C./40 Pa (0.3 mm Hg).

IR: νC=0: 1680 cm¹ ; νNH: 3280 cm¹.

¹ H NMR (CDCl₃, TMS): 1.3 ppm triplet CH₃ 3.95 ppm doublet ##STR61## 4.2ppm quartet CH₂ (CH₃) 5.1 ppm singlet ##STR62## 5.2 ppm broad singlet NH6.4 ppm complex H--C═ 7.4 ppm complex ##STR63##

EXAMPLE 30 Preparation of benzyloxycarbonyl-L-proline

To a solution of 1.15 g (10 mmol) of L-proline in 10 ml of methanol and3 ml of saturated aqueous K₂ CO₃, 2.36 g (11 mmol) of benzylα-chloroethyl carbonate are added at 5° C. After 4 hours of reaction, 50ml of water are added and the mixture is washed with twice 10 ml ofethyl ether. The mixture is acidified to pH 2-3 with 6N HCl andextracted with ethyl acetate.

After evaporation of the solvents and crystallisation in an ethylacetate/petroleum ether mixture, 2.2 g (88% yield) of Z-(L)-Pro areobtained.

M.p. 75°-76° C. (m.p._(Lit). 76°-78° C.).

EXAMPLE 31 Preparation of 1,2,2,2-tetrachloroethyl 2-trimethylsilylethylcarbonate ##STR64##

The procedure is as in Example 21(a). Starting with 5.91 g oftrimethylsilylethanol and 12.35 g of tetrachloroethyl chloroformate,13.6 g (83% yield) of the expected product are obtained.

B.p. 92°-94° C./6.6 Pa.

IR νCO=1750 cm⁻¹.

¹ H NMR (CDCl₃, external TMS): 0.1 (s, CH₃ --Si) 1.1(t, CH₂ --Si)4.35(t, CH₂ --O) 6.7(s, CH--Cl)

EXAMPLE 32 Preparation of trimethylsilylethyloxycarbonyl-L-phenylalanine##STR65##

0.83 g of L-phenylalanine (5 mmol) is dissolved in a dioxane/water (1:2)mixture (12 ml) containing 1.4 ml of triethylamine (10 mmol). Themixture is cooled to 0° C. and 1.8 g (5.5 mmol) of the above carbonatedissolved in 4 ml of dioxane is added in a single portion. After 2 hoursat 0° C., 20 ml of water are added and the mixture is extracted withtwice 20 ml of ether. The aqueous phase is then acidified (pH 2-3) with6N HCl, and extracted with 3 times 50 ml of ethyl acetate. The extractis dried over MgSO₄ and evaporated. 1.4 g (100% yield) of the expectedproduct is obtained in the form of an oil.

¹ H NMR (CDCl₃, TMS) O(s,CH₃ --Si) 0.9(t, CH₂ --Si) 3.0(CH₂ Ph);4.0(t,O-CH₂ -C-Si) ##STR66##

2 ml of dicyclohexylamine are added to this oil dissolved in 5 ml ofether and, after crystallisation, 1.93 g (78% yield) ofdicyclohexylammonium salt is collected, M.p. 111°-112° C.

What is claimed is:
 1. A process for preparing carbamic acid derivativesof formula ##STR67## wherein R₁ and R₂, are the same or different, andare: hydrogen,an aliphatic radical having from 1 to 20 carbon atoms, acycloaliphatic or araliphatic radical having up to 50 carbon atoms, ortogether with the nitrogen atom to which they are attached, form apiperidino, morpholino or imidazolyl ring, said aliphatic,cycloaliphatic, araliphatic radical and said ring being unsubstituted orsubstituted with acid, alcohol, ester, ether, mercapto or amino groups,and wherein Y is ##STR68## group in which: (i) R denotes:an aliphaticradical having from 1 to 12 carbon atoms, said radical beingunsubstituted or substituted by halogen atoms or with a furyl ortrimethylsilyl radical; a benzyl or nitrobenzyl radical, a phenyl,benzofuranyl or fluorenylmethyl radical, said benzofuranyl radical beingunsubstituted or substituted with lower alkyl; (ii) R₃ and R₄ are thesame or different, and are hydrogen, methyl or together with thenitrogen atom to which they are attached form an imidazolyl ring, (iii)and R₆ and R₇, are the same or different and are C₁ to C₁₂ aliphaticradical or a cycloaliphatic radical with up to 30 carbon atoms,unsubstituted or substituted by lower alkylthio radical or are ahydrogen, a methylthio radical, lower alkyloxy radical, which consistsof reacting an amino compound of formula ##STR69## in the presence of anacceptor for hydrohalic acid, at a temperature between -5° C. and 150°C., with an alphahalogenated derivative of carbonic acid of formula:##STR70## in which R₁, R₂ and Y are as defined hereinabove, X is afluorine, chlorine or bromine atom and R₅ is an aliphatic radical of 1to 4 carbon atoms and is unsubstituted or substituted with halogenatoms.
 2. The process according to claim 1, wherein X denotes a chlorineatom.
 3. The process according to claim 1, wherein the α-halogenatedderivative is α-chloroethyl ethyl carbonate, α-chloroethyl tert-butylcarbonate, α-chloroethyl furfuryl carbonate, α-chloroethyl benzylcarbonate, α-chloroethyl phenyl carbonate or α-chloroethyl2,3-dihydro-2,2-dimethyl-7-benzofuranyl carbonate,1,2,2,2-tetrachloroethyl tert-butyl carbonate, α-chloroethyl S-ethylthiocarbonate, α-chloroethoxyimidazole, 1,2,2,2-tetrachloroethylN-methylcarbamate, 1,2,2,2-tetrachloroethyl 2-trimethylsilylethylcarbonate, or 2-methyl-2-(methylthio)propanalO-[α-chloroethyloxycarbonyl]oxime.
 4. The process according to claim 1,whereinthe amine is methylamine, diethylamine, di-n-butylamine,isobutylamine, n-octylamine, ethanolamine, benzylamine, imidazole,hexamethyleneimine, morpholine, diethanolamine, N-methyl-N-benzylamine,piperidine, L-phenylalanine, L-proline, glycine, L-tyrosine, L-serine,L-aspartic acid, ethyl glycinate, phenylglycine or proline.
 5. Theprocess according to claim 1, whereinthe reaction is performed in thepresence of one or more solvents which are inert with respect to thereagents.
 6. The process according to claim 1, wherein the solvent is amember selected from the group consisting of chlorinated aliphaticsolvents, cyclic or acyclic ethers, alcohols, acetone, pyridine,acetonitrile and dimethylformamide.
 7. The process according to claim 5,whereinthe solvent medium contains water.
 8. The process according toclaim 1, whereinthe acceptor for acid is an organic or inorganic base.9. The process according to claim 1, whereinthe acceptor for acid issodium hydroxide or potassium hydroxide, sodium sulphite, sodiumcarbonate or bicarbonate or potassium carbonate or bicarbonate,magnesium oxide, a tertiary amine or the starting amine of formula##STR71## R¹ and R² having the significance above.
 10. The processaccording to claim 1, wherein the tertiary amine is triethylamine,pyridine or N,N-dimethylaniline.
 11. The process according to claim 1wherein R is tert-butyl, benzyl, para-nitrobenzyl, 9-fluorenylmethyl,2,2,2-trichloroethyl, trimethylsilylethyl or furfuryl.
 12. The processaccording to claim 1 wherein R₁ and R₂ are the radical ofL-phenylalanine, L-proline, glycine, L-tyrosine, L-serine, L-asparticacid, proline, ethyl glycinate and phenylglycine.
 13. The processaccording to claim 1, wherein R is an furfuryl, benzyl or phenyl. 14.The process according to claim 1, wherein the α-halogenated derivativeis chloromethyl t.butyl carbonate.